Many hormones and neurotransmitters regulate biological functions via specific receptor proteins on the cell membrane. Most of these receptor proteins carry out intracellular signaling via the activation of coupled guanosine triphosphate-binding proteins (G proteins). These receptor proteins are collectively called “G protein-coupled receptor proteins”, or “seven-transmembrane receptor proteins”, owing to their common structure comprising seven transmembrane domains.
G protein-coupled receptor proteins exist on the surface of living cells and various functional cells in organs. These receptor proteins play exceedingly important roles as targets of various molecules that regulate the functions of cells and organs, for example, hormones, neurotransmitters, physiologically active substances and such. Therefore, G protein-coupled receptor proteins have attracted attention as targets in developing pharmaceutical agents.
Histamine receptor H3 protein is a type of G protein-coupled receptor protein. Genes encoding the protein have been reported in various organisms including humans (Lovenberg T. W. et al., Molecular Pharmacology, 55: 1101-1107, 1999; Lovenberg T. W. et al., Journal of Pharmacology and Experimental Therapeutics, 293: 771-778, 2000; Tardivel-Lacombe J. et al., Molecular Neuroscience 11: 755-759, 2000).
To date, analysis of the action mechanism of the histamine receptor H3 protein has been carried out using its agonists and antagonists.
Administering cats with R-α-methylhistamine (RAMH), a histamine receptor H3 protein agonist, causes a significant increase in deep slow-wave sleep. This effect is reversed by administration of thioperamide, a histamine receptor H3 protein antagonist. Conversely, waking effects were observed upon thioperamide administration, an effect antagonized by RAMH. Thus the histamine receptor H3 protein may be involved with sleep (Lin J. S. et al., Neuropharmacology 27: 111-122, 1988).
Administration of RAMH decreases voluntary movement in rats and mice. Conversely, thioperamide exhibits anxiety-inducing effects in mice. PET scans show high concentrations of histamine receptor H3 protein at a site in the brain considered to be related to attention deficit hyperactivity disorder (ADHD). Furthermore, drugs comprising sedative or anti-anxiety effects, such as clinidine (α-2 agonist), 8-OH-DPAT (acts on 5HT), diazepam, and buspirone, have been reported to reduce histamine neuron metabolic turnover. Therefore, histamine receptor H3 protein may be involved with antianxiety effects (Schwartz J. C. et al., Histaminergic Neurons: Morphology and Function. CRC Press 85-104, 1991).
There are many reports that activation of histamine neurons leads to improvement of memory and learning, while histamine receptor H1 protein antagonists and histamine biosynthesis inhibitors cause their deterioration. Furthermore, in human Alzheimer's disease patients, histamine levels in the cerebrospinal fluid are reduced. This is also observed in Down's syndrome patients, and is considered a common phenomenon among patients with learning disabilities. Thioperamide exhibits an effect in improving learning in senescence-accelerated mice with learning disabilities. Thioperamide also shows both histamine dissociation and acetylcholine dissociation promoting activity. Therefore, the histamine receptor H3 protein may be involved with memory and learning functions (Mochizuki T. et al., Naunyn-Schmiedberg's Archieves Pharmacology 343: 190-195, 1991).
Intracerebral administration of histamine to mice results in analgesic and/or algesic action, depending on the dose. Histamine receptor H1 protein antagonists show potentiation of morphine's analgesic effect, whilst histamine receptor H2 protein antagonists show attenuation. Thioperamide administration shows attenuation of analgesia, due to stimulation of the histamine receptor H1 protein. Since the analgesic effect of thioperamide is antagonized by RAMH, the histamine receptor H3 protein may be involved with analgesic effects (Onodera K. et al., Progress in Neurobiology 42: 685-702, 1994).
Histamine receptor H3 protein agonists are reported to constrict blood vessels and may therefore be effective towards pain such as human migraine headaches, which result from cerebrovascular dilation. Histamine receptor H3 protein is expressed in primary afferent sensory neurons (C-fibers). Histamine suppresses the dissociation of neuropeptides such as substance P and neurokinin. These neuropeptides act to dilate and increase the permeability of dural blood vessels, causing inflammation and pain. The histamine receptor H3 protein constricts blood vessels, and may comprise the function of being effective for pain (Mansfield L. E. Journal of Allergy and Clinical Immunology 86: 673-676, 1990).
Electroconvulsion experiments used as an experimental epilepsy model showed that histamine neurons were involved in a system for inhibiting convulsions via the histamine receptor H1 protein. Electroconvulsion can be suppressed by administration of thioperamide or Clobenpropit, which are antagonists of the histamine receptor H3 protein. These effects seem to result from dissociation of histamine by histamine receptor H3 protein agonists, and suppression of convulsions by this histamine through the histamine receptor H1 protein. Therefore, the histamine receptor H3 protein may be involved with the action of suppressing convulsions (Yokoyama H. et al., European Journal of Pharmacology 234: 129-133, 1993).
Histamine receptor H3 protein antagonists suppress gastric acid secretion by suppressing the release of histamine, acetylcholine and somatostatin from the vagus nerve, enterochromaffin-like cells and D-cells (somatostatin releasing cells). The histamine receptor H3 protein may therefore be involved with gastric acid secretion.
Histamine receptor H3 protein is expressed in primary afferent sensory nerves (C-fibers) and inhibits the release of neuropeptides by working in combination with histamine-releasing mast cells. A feedback mechanism is expressed in the respiratory system, and histamine receptor H3 protein may be involved with asthma (Ichinose M. et al., British Journal of Pharmacology 97: 13-15, 1989).
The histamine receptor H3 protein exists in sympathetic nerve endings in the circulatory system, and inhibits norepinephrine release. In chronic myocardial infarction, norepinephrine release is increased. The histamine receptor H3 protein is activated by mast cell histamines. Histamine H3 receptor protein agonists inhibit transduction in the sympathetic nervous system, and may become therapeutic agents for arrhythmia, myocardial infarction, and such. Furthermore, histamine receptor H3 protein agonists promote CGRP release. Since CGRP is increased in sepsis, heart failure, and acute myocardial infarction, such agonists may be effective for these diseases. Therefore, the histamine receptor H3 protein may be involved with circulatory function (James G. P. et al., Ann. Rep. Med. Chem. 33: 31-40, 1998).
Furthermore, administration of a histamine receptor H3 protein antagonist has been reported to reduce food intake in test animals (Ookuma K. et al., Brain Res. 628: 235-242, 1993; PCT/US94/11790).
However, studies such as those described above, using histamine receptor H3 protein agonists and antagonists, are known to influence a variety of parameters, perhaps due to compound specificity or pharmaceutical agent dose. Thus it is difficult to apply studies which use agonists and antagonists to actually determine a direct relationship between the histamine receptor H3 protein and changes in body weight or food intake.
Histamine receptor H3 protein exists at high concentrations in the feeding center, but to date there has been no report of a direct relationship between the histamine receptor H3 protein and bulimia, anorexia, or obesity.